Proteoglycan compositions for treatment of inflammatory diseases

ABSTRACT

Compositions with synergistic anti-inflammatory effects in inflammatory diseases resulting from activation and consequent degranulation of mast cells and followed by secretion of inflammatory biomolecules from the activated mast cells, composed of, as active ingredients, a heavily sulfated, non-bovine proteoglycan such as shark cartilage chondroitin sulfate C and an unrefined olive kernel extract that increases absorption of these compositions in various routes of administration, plus one or more of a hexosamine sulfate such as D-glucosamine sulfate, a flavone such as quercetin, S-adenosylmethionine, a histamine-1 receptor antagonist, a histamine-3 receptor agonist, an antagonist of the actions of CRH, caffeine, and a polyamine.

[0001] This application is a continuation/divisional of co-pending PCT/US02/00476, filed Jan. 03, 2002, which is a continuation of co-pending U.S. Ser. No. 09/771,669, filed Jan. 30, 2001.

BACKGROUND OF THE INVENTION

[0002] The invention is generally related to the treatment of inflammatory conditions. More specifically, the invention is related to compositions containing inhibitors of mast cell activation and secretion such as a proteoglycan that are designed to be used as dietary supplements or adjuvants to conventional approved medications for the relief of inflammatory conditions.

[0003] There have been a number of mostly anecdotal reports that the proteoglycan chondroitin sulfate, as well as glucosamine sulfate, a product of the intestinal breakdown of proteoglycans, may be helpful in relieving the pain of osteoarthritis:—Shute N. Aching for an arthritis cure. US News and World Report, Feb. 10, 1997.—Cowley G. The arthritis cure? Newsweek, Feb. 17, 1997; Foreman J., People, and their pets, tout arthritis remedy. The Boston Globe, Apr. 7, 1997; Tye L. Treatment gains scientific attention. The Boston Globe, Sep. 25, 2000.

[0004] A recent meta-analysis showed potential therapeutic benefit of chondroitin ulfate and/or glucosamine in osteoarthritis [McAlindon et al. J Am Med Assn. 283:1469 (2000)], while a double-blind clinical trial with glucosamine showed definite benefits in osteoarthritis with respect to both pain and radiographic joint appearance [Reginster et al., Lancet 337:252 (2001)]. However, less than 5% of the chondroitin sulfate in commercially available preparations is absorbed orally, because the size of the molecule and the degree of sulfation impede its absorption from the gastrointestinal tract. Furthermore, such commercial preparations use chondroitin sulfate obtained from cow trachea, with the possible danger of contracting spongiform encephalopathy or “mad cow disease”. In fact, the European Union has banned even cosmetics that contain bovine-derived products.

[0005] Theoharides et al. British Journal of Pharmacology 131:1039 (2000) indicated for the first time how proteoglycans such as chondroitin sulfate may work. The paper reported that chondroitin sulfate and, to a lesser degree, glucosamine sulfate, inhibit activation of mast cells that are known to trigger allergy and asthma. This discovery is the basis for Theoharides, U.S. patent application Ser. Nos. 09/056,707, filed Apr. 8, 1998 and 09/773,576, filed Feb. 2, 2001.

[0006] Mast cells are also now recognized as important causative intermediary in many painflul inflammatory conditions [Galli, N Eng J Med. 328:257 (1993); Theoharides, Int J Tissue Reactions 18:1 (1996)], such as interstitial cystitis and irritable bowel syndrome [Theoharides, Ann NY Acad, Sci. 840:619 (1998)], as well as in migraines and possibly multiple sclerosis [Theoharides, Persp Biol Med. 26:672 (1983); Theoharides, Life Sci 46:607 (1996)]. In fact, glucosamine was recently considered to be prophylactic for migraines [Russell, Med Hypoth 55:195 (2000)].

[0007] Mast cells are increasingly implicated in conditions involving inflamed joints, such as in osteoarthritis and rheumatoid arthritis, through activation of local mast cells by, for example, neuropeptides, such as Substance P. Additional indirect evidence also supports the involvement of mast cells in bone resorption: (a) systemic mastocytosis is invariably associated with osteoporosis; (b) inhibition of mast cell mediator release reversed lytic bone changes; (c) depletion of mast cells inhibited bone resorption in organ culture; (d) human synovial mast cells were shown to secrete in response to allergic and non-immunologic stimuli; (e) human mast cells release the cytokine IL-6 and (f) IL-6 has been definitively linked to bone resorption and osteoporosis.

[0008] It was recently shown that chondroitin sulfate's ability to inhibit the activation of mast cells compliments the inhibitory effects on mast cell activation of another class of naturally occurring compounds, the flavonoids [Middleton et al. Pharm Rev 52:1 (2000)]. Certain plant flavones (in citrus fruit pulp, seeds, sea weed) are now recognized as anti-allergic, anti-inflammatory, anti-oxidant and cytoprotective with possible anti-cancer properties. Only some flavonoids that belong to the subclass of flavones, e.g., quercetin, inhibit mast cell activation.

[0009] Quercetin inhibits secretion from human activated mast cells [Kimata et al. Allergy 30:501(2000)], and has also been used effectively for the treatment of chronic prostatitis [Shoskes et al., Urology 54:960 (1999)]. However, other flavonoids may have opposite effects. Use of the term “bioflavonoids” or “citrus flavonoids” in certain commercial products, therefore, provides little information, and may include molecules that have detrimental effects; for example, soy contains isoflavones that have estrogen-like activity that worsens inflammatory conditions.

[0010] Copending U.S. patent application Ser. Nos. 09/056,707, filed Apr. 8, 1998, and divisional 09/773,576 claim the oral use of proteoglycans, without and with flavonoids, for the treatment of mast cell activation-induced diseases. Absorption of these compositions from the gastrointestinal tract and synergism with other treatment modalities were not addressed in these applications.

[0011] Applicant has described the use of antagonists of the action of Corticotropin Releasing Hormone (also known as Corticotropin Releasing Factor) in inhibiting myocardial mast cell activation in myocardial ischemia (copending U.S. patent application Ser. No. 08/858,136, filed May 18, 1997), in treating stress-induced skin disease (U.S. Pat. No. 6,020,305) and stress-induced migraine headaches (U.S. Pat. No. 5,855,884), the contents of which are incorporated herein by reference. The synergistic effects of the compositions of the present invention that include antagonists of the actions of Corticotropin Releasing Hormone (“CRH”) on mast cells were not recognized at the time of the previous studies. The word “antagonists” in connection with CRH is intended herein to include any molecule that prevents the actions of CRH on target cells, and includes, but is not limited to, anti-CRH neutralizing antibodies or binding proteins, or molecules preventing the release of CRH at local sites (see below for details).

[0012] Applicant has also described a method for treating patients with mast cell derived molecules-induced interstitial cystitis with histamine-1 receptor antagonists (U.S. Pat. No. 5,994,357). Treatment of mast cell molecules-induced migraines with histamine-1 receptor antagonists is the subject of Theoharides U.S. Pat. No. 5,855,884. Histamine-3 receptor agonists as pharmaceutical agents in mast cell-involved diseases are described in Theoharides U.S. Pat. No. 5,831,259. The contents of these three patents are incorporated herein by reference. At the time of this invention the synergistic effects of the present compositions with such antagonists had not yet been recognized.

[0013] An important need therefore exists for compositions for administration to human patients being treated for mast cell-induced inflammatory diseases by various modalities, that are synergistic in that they have stronger effects than the sum of the effects of the individual components, and also synergistic with conventional clinical treatments of inflammatory conditions. “Synergistic” is also intended to mean: “coordinated or correlated action by two or more structures or drugs” [Stedman's Medical Dictionary, 23rd edition, Williams & Wilkins, Baltimore, 1976]. An important need also exists for formulations that increase the absorption from the gastrointestinal tract, nasal passages and skin surface of the compositions of the invention. Such formulations have been discovered, and are described below.

SUMMARY OF THE INVENTION

[0014] The invention comprises compositions for human use containing a sulfated proteoglycan and an unrefined olive kernel (seed) oil, and one or more active ingredients selected from the group consisting of a sulfated hexosamine, a flavonoid compound, S-adenosylmethionine (“SAM”), histamine-1 receptor antagonists, histamine-3 receptor agonists, antagonists of the actions of CRH, caffeine, folic acid, rutin, polyunsaturated fatty acids, and polyamines, together with appropriate excipients and carriers, said compositions having improved absorption from the gastrointestinal tract, skin surface, and nasal and pulmonary surfaces, and anti-inflammatory effects synergistic with each other and synergistic with available conventional clinical treatment modalities.

[0015] In one embodiment, the sulfated glucosamine is D-glucosamine sulfate, the proteoglycan is non-bovine chondroitin sulfate, and the flavone is quercetin.

[0016] In an other embodiment, compositions may also contain antagonists of the effects of CRH on mast cells or other target cells of the myocardium, gastric mucosa, urinary bladder, skin, meningeal membranes, and blood-brain barrier.

[0017] In still another embodiment, the present compositions are used against superficial vasodilator flush syndromes.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS OF THE INVENTION

[0018] It has been discovered that a combination of a sulfated proteoglycan and a unique olive kernel extract, together with one or more of a sulfated D-hexoseamine, a flavone, CRH antagonists, histamine-1 receptor antagonists, histamine-3 receptor agonists, polyamines and caffeine has synergistic anti-inflammatory effects when used as a dietary supplement, a topical product or an aerosol for nasal or pulmonary adminstration, without or with a conventional clinical treatment for inflammatory diseases. Such inflammatory diseases result from the activation, degranulation and consequent secretion of inflammatory biochemicals from mast cells, and the resultant inflammatory diseases include the group consisting of: allergic inflammation, arthritis (to include osteoarthritis and rheumatoid arthritis), cancer, fibromyalgia, inflammatory bowel disease, interstitial cystitis, irritable bowel syndrome, migraines, angina, chronic prostatitis, eczema, multiple sclerosis, psoriasis, sun burn, periodontal disease of the gums, superficial vasodilator (flush} syndromes and hormonally-dependent cancers.

[0019] In a highly preferred embodiment, the sulfated proteoglycan is non-bovine chondroitin sulfate, preferably from shark cartilage, which blocks mast cell activation, degranulation and consequent secretion of inflammatory biochemicals from the mast cells. Other natural sulfated proteoglycans suitable for practicing this invention include keratan sulfate, dermatan sulfate and hyaluronic acid sodium salt (sodium hyaluronate). A preferred biological source of the chondroitin sulfate is shark cartilage which is more-highly sulfated than the common commercial chondroitin sulfate isolated from cow trachea; the shark cartilage source also avoids the potential dangers associated with bovine sources.

[0020] The highly preferred flavone is quercetin which inhibits secretion of inflammatory molecules from mast cells by affecting moesin, a unique 78 kDa mast cell protein [Theoharides et al. J Pharm Exp Therap 294:810 (2000)]. In addition to quercetin, other flavones suitable in carrying out the invention include myricetin, genistein, kaempferol and the quercetin glycoside rutin. A highly preferred source of quercetin and its glycoside is the Saphona plant.

[0021] The olive kernel (pit) extract component of the inventive compositions is preferably an unrefined (first pressing, filtered, oleic acid-related acidity <1%, water content <5%) oil produced, for one source, on the island of Crete in Greece. This kernel oil is especially prepared by the maker by a process consisting essentially of: (1) washing the kernel mass that remains after the compression of the oil from the olive flesh with water (Sansa); (2) drying the washed kernels in a stream of hot air at about 80 degrees C. to reduce the humidity to about 1%; (3) extracting the dried kernels with hexane and steam; (4) cooling the hexane extract, microfiltering the extract (5 micron pore size) to remove particulate matter; (5) heating the hexane extract at about 40 degrees C. degrees while percolating helium (to avoid oxidation) through the fluid to evaporate the hexane (final <0.5%), which process reduces the water content to <1% and the acidity (as oleic acid) to <3%; and (6) storing the extract in sealed containers. This olive kernel extract surprisingly has the unique property of increasing absorption of the other components of the anti-inflammatory compositions through the intestinal mucosa and skin, and also adds its own content of important anti-oxidants [Bosku, World Rev Nutr Diet, 87:56 (2000)], such as omega fatty acids (e.g., eicosapentanoic acid) and alpha tocopherol. Although not claimed herein, it has been claimed that kernel olive extract has cytoprotective, longevity-producing effects [Trichopoulou et al. Am J Clin Nutr 61:1346S (1995); Trichopoulou et al, Cancer Epid Biomarker Prevention 9:869 (2000)]. The polyphenols in such olive kernel extracts also have anti-inflammatory effects in, for example, arthritis [Martinez-Dominguez et al., Inflamm. Res. 50:102 (2001)]. A preferred source of the unrefined olive kernel extract of the invention is: E.B.E.K., Inc., Commercial, Industrial Enterprises of Crete, 118 Ethnikis Antistasecos, Heraklion, Crete, 71306, Greece.

[0022] Supplementation of the compositions described above with the methylation reagent S-adenosylmethionine (“SAM”) adds antioxidant, anti-inflammatory and cytoprotective properties, particularly in inflammatory joint diseases. Addition of SAM also accelerates metabolism of homocysteine, which amino acid has been implicated in coronary disease, to cysteine, which is harmless. Folic acid may be added to certain of the present formulations for similar reasons.

[0023] Another supplement to the basic compositions of the invention is a histamine-1 receptor antagonist, such as diphenhydramine, hydroxyzine, azelastine, azatadine and cyproheptadine. Other suitable histamine-1 receptor antagonists are described in Table 25-1 in Goodman and Gilman's The Pharmaceutical Basis of Therapeutics, 9^(th) ed., New York, 1996. Suitable histamine-3 receptor agonists are described in the Theoharides patents listed above.

[0024] Inhibitors of mast cell activation and secretion may be used in the treatment of inflammatory processes such as superficial vasodilator syndrome, e.g., menopausal-associated flush, monosodium glutamate-associated flush, carcinoid flush and niacin-associated flush.

[0025] Sources of CRH antagonists include, in addition to the Theoharides patents listed in the Background section above: Neurocrine Biochem. Inc.'s D-Phe 12 NIe Ala32,21,38hCRH(12-41)NH2, cat no. 1P-36-41; Pfizer non-peptide CP-154,526-1; Sigma Chem., St. Louis anti-CRH polyclonal antiserum; and Pfizer, NY patents and applications: U.S. Pat. No. 6,211,195, U.S. Pat. No. 5,795,905, PCT/IB95/00573, PCT/IB95/00439, U.S. Ser. No. 08/448,539, U.S. Ser. No. 08/481,413, U.S. Ser. No. 09/735,841, and in Owens et al. Pharm. Rev. 43:425 (1991).

[0026] The preferred concentration range of the proteoglycan, hexosamine sulfate and flavone components of the oral formulations are 10-3,000 mg per tablet or capsule. The preferred concentration range for SAM is 3-1,000 mg per capsule or tablet. Generally, the amounts of th unrefined kernel extract are at least three times those of the oth r active ingredients, preferably 900-1200 mg, although lower amounts, e.g., 50 mg may also be effective.

[0027] The number of capsules or tablets to be taken per day is determined by the nature and severity of the medical condition, and is readily determinable by the patient's health provider. Other representative formulations are described in the examples below.

[0028] The compositions of the invention may be formulated in any standard means of introducing pharmaceuticals into a patient, e.g., by means of tablets or capsules. The compositions of the invention include ointments and creams for skin conditions, mouth washes and toothpaste for periodontal diseases, and solutions for nasal aerosols. Standard excipients and carriers for the active ingredients of the inventive compositions are described in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. Fragrances and flavorings may also be added.

[0029] Although not bound by any particular mechanism of action of the components of the claimed compositions, the inventor contemplates that the proteoglycan inhibits the activation and degranulation of the relevant mast cells, while the flavone inhibits the secretion of inflammatory biomolecules from these mast cells. “Activation” and “degranulation” of mast cells are defined herein as is standard and well known in this art, that is, to mean secretion from the activated mast cell of any type of molecule(s) that alone or in combination triggers inflammatory processes.

EXAMPLES Example 1

[0030] Table 1 compares chondroitin sulfate-containing commercial products to the present compositions. TABLE 1 Comparison of Chondroitin Sulfate-Containing Products to Present Invention Most Available Product Compositions Present Invention Main ingredient Mixture of chondroitins Non-bovine chondroitin sulfate, preferably the C type Source Cow trachea Shark cartilage Amount per cap- 100-300 10-3000 mg sule or tablet Degree of sulfa- Low, if any High tion Absorption from <5% >15% g.i. tract Target Unknown Mast cells, inflammatory cells Other ingredients Vitamins, fish Flavones, unrefined oils (some preparations) kernel olive oil, SAM, histamine-1 receptor antagonists, histamine-3 receptor agonists, CRH antagonists, polyamines, caffeine, folic acid Advantages None known Anti-allergic, anti- inflammatory, anti- oxidant, cytoprotective Adverse effects Risk of mad cow None known disease, spongiform encephalopathy, stomach upset, allergy to fish products Relevant condi- Osteoarthritis Allergic inflammation tions angina, asthma coronary artery disease, arthritis (osteoarthritis or rheumatoid arthritis), chronic prostatitis, eczema, fibromyalgia, interstitial cystitis, irritable bowel syndrome, inflammatory bowel disease, migraines, multiple sclerosis, psoriasis, periodontal disease, flush syndrome, cancer (including hormonally-dependent forms). Scientific publica- None found Theoharides et al. Br J tions Pharm 131: 1039 (2000) Middleton et al. Pharm Rev 52: 673 (2000)

[0031] In all examples, chondroitin sulfate is to assumed to be of a non-bovine variety.

Example 2

[0032] Composition For Protecting Against Inflammatory Diseases) Two capsul s to be taken orally 2-3 times daily, at least one hour before meals Ingredients, per capsule, mg: Chondroitin sulfate 150-300 Unrefined olive kernel extract  900-1200 D-Glucosamine sulfate 150-300 Quercetin 150-300

Example 3

[0033] Composition For Protecting Against Arthritis Ingredients per capsule, mg: D-Glucosamine sulfate 150-300 Unrefined olive kernel extract  900-1200 Chondroitin sulfate 150-300 Sodium hyaluronate 100-200 Quercetin 150-300

Example 4

[0034] Topical Composition For Protecting Against Arthritis Skin ointment or cream. Apply three times per day to affected areas. Ingredients % by weight D-glucosamine sulfate 5 Unrefined olive kernel extract 15 Chondroitin sulfate 5 Sodium hyaluronate 5 Bitter willow bark extract 5 Quercetin 3

Example 5

[0035] Composition For Protecting Against Cardiovascular Disease Two capsules to be taken orally 2-3 times per day, in mg: Chondroitin sulfate  50 Unrefined olive kernel extract 900-1200 Kaempferol 100 S-adenosylmethionine  50 Niacin 100 Bitter willow bark extract, 5% by weight

Example 6

[0036] Composition For Protecting Against Periodontal Disease Mouthwash: Chondroitin sulfate 0.4 M Quercetin 0.4 M In a standard mouthwash vehicle

Example 7

[0037] Toothpaste Composition Toothpaste, mg %: Chondroitin sulfate 5 Quercetin 3 Optionally, D-glucosamine sulfate 5 In a standard toothpaste vehicle

Example 8

[0038] Sunscreen Composition Ingredients mg % Unrefined olive kernel extract 900-1200 Chondroitin sulfate 5 D-glucosamine sulfate 5 Quercetin 3 Sun screen (e.g., TiO₂) 5

Example 9

[0039] Composition For Protecting Against Migraine Headaches Ingredients, mg: Chondroitin sulfate 50 Quercetin 100 Azatadine 4 Optionally, a CRH-receptor antagonist

Example 10

[0040] Composition For Protecting Against Relapsing Multiple Sclerosis Ingredients, mg: Chondroitin sulfate 50 Quercetin 400 Hydroxyzine 50 Optionally, interferon-beta

Example 11

[0041] Composition For Protecting Against Cystitis And Prostatitis Ingredients, mg: D-glucosamine sulfate  50 Chondroitin sulfate 100-300 Sodium hyaluronate 200 Quercetin 100-400

Example 12

[0042] Composition For Protecting Against “Flush” Ingredients, per capsule: Chondroitin sulfate 50 mg Quercetin 150 mg Bitter willow bark extract 5% by weight Optionally, cyproheptadine or 4 mg azatadine

Example 13

[0043] Cream Composition For Protecting Against Skin Allergy Ingredients: % by weight Unrefined olive kernel extract 15 Non-bovine chondroitin sulfate 5 Myricetin 5 Alpha-tocopherol 5 Aloe vera 5 Optionally, azelastine or hydroxyzine 5

Example 14

[0044] Composition For Protecting Against Allergy and Allergic Asthma Ingredients, mg Myricetin 500 Chondroitin sulfate 200 Optionally, azelastine or hydroxyzine

Example 15

[0045] Composition For Protecting Against Hormonally-Dependent Cancers Ingredients, mg Quercetin 150 Genestein 50 Optionally, tomoxifen or raloxifen 10

Example 16

[0046] Composition For Protecting Against Allergic Conjunctivitis Ingredients: Quercetin 0.05% Chondroitin sulfate  2.0% Optionally, azelastine 0.05%

Example 17

[0047] Composition for Treating Arthritic Conditions Ingredients: Mg/tablet or capsule Unrefined olive kernel extract 430 Non-bovine chondroitin sulfate 200 Quercetin · HCl 150 Sodium hyaluronate 20 Bitter willow extract 30 S-adenosylnethionine 20

Example 18 Effect of Olive Kernel Extract on Absorption of Proteoglycan Sulfate In Vivo

[0048] Chondroitin sulfate was tritiated by New England Nuclear Corp. to a specific activity of 4.3 mCi/ml.

[0049] 2.5 mCi of tritiated chondroitin sulfate was given orally to 250 g laboratory rats without (control) and with (experimental) olive kernel extract (OKE}. Serum radioactivity was measured 8 hours thereafter.

[0050] The results showed that, in control animals, about 3.9% of the dose reached the circulation. In sharp contrast, in animals given OKE along with the labeled chondroitin sulfate, about 14.3% of the dose was absorbed into the general circulation.

[0051] These results demonstrate that OKE increased by almost 400% the absorption of a proteoglycan from the intestine into the general circulation. 

I claim:
 1. A composition with synergistic anti-inflammatory properties in conditions induced by th activation of mast cells, consequent degranulation of said cells and secretion of inflammatory biomolecules, comprising a non-bovine proteoglycan sulfate and an unrefined olive kernel extract, plus one or more of a hexosamine sulfate, a flavone,, S-adenosylmethionine (“SAM”), a histamine-1 receptor antagonist, a histamine-3 agonist, an antagonist of the actions of Corticotropin Releasing Hormone (“CRH”), a hyaluronate salt, a rutin, a polyamine, and caffeine, in an appropriate excipient or vehicle.
 2. The composition according to claim 1, wherein said sulfated proteoglycan is selected from the group consisting of non-bovine chondroitin sulfate, keratan sulfate, dermatan sulfate and sodium hyaluronate.
 3. The composition according to claim 2, wherein said chondroitin sulfate is chondroitin sulfate C derived from shark cartilage.
 4. The composition according to claim 1, wherein said hexosamine sulfate is D-glucosamine sulfate.
 5. The composition according to claim 1, wherein said flavone is selected from the group consisting of quercetin, myricetin, genistein and kaempferol.
 6. The composition according to claim 1, wherein said unrefined olive kernel extract contains polyphenols and alpha-tocopherol.
 7. The composition according to claim 1, said composition being for oral use, comprising 10-3,000 mg per capsule or tablet of each of non-bovine chondroitin sulfate C, quercetin and D-glucosamine sulfate, with 900-1200 mg unrefined olive kernel extract.
 8. The composition according to claim 7, further supplemented with 3-1,000 mg of SAM per capsule or tablet.
 9. A composition according to claim 1, wherein said inflammatory diseases are selected from the group consisting of: arthritis, cancers, fibromyalgia, inflammatory bowel disease, interstitial cystitis, irritable bowel syndrome, migraines, angina, chronic prostatitis, eczema, multiple sclerosis, psoriasis, sun burn, tooth decay, periodontal disease, stressed-induced migraines, stress-induced opening of bladder mucosa, stress-induced opening of the blood-brain barrier, superficial vasodilator(flush} syndrome, and hormonally-dependent cancers.
 10. The composition according to claim 9, wherein said inflammatory disease is arthritis and said composition is for oral administration, comprising non-bovine chondroitin sulfate, quercetin, D-glucosamine sulfate, unrefined kernel olive oil, and, optionally, sodium hyaluronate.
 11. The composition according to claim 9, wherein said inflammatory disease is arthritis and said composition is for topical use, comprising D-glucosamine sulfate, non-bovine chondroitin sulfate, sodium hyaluronate, bitter willow bark extract, quercetin and unrefined olive kernel extract.
 12. The composition according to claim 9 for oral or aerosol use in allergicconditions, comprising non-bovine chondroitin sulfate and a flavonoid selected from the group consisting of quercetin, myricetin and kaempferol, unrefined kernel olive oil, and, optionally, a histamine-1 receptor antagonist.
 13. The composition according to claim 9, for topical use in allergic conditions, comprising non-bovine chondroitin sulfate, myricetin, alpha-tocopherol, unrefined kernel olive oil, and, optionally, a histamine-1-receptor antagonist.
 14. The composition according to claim 13, wherein said antagonist is diphenhydramine, hydroxyzine, azatadine, azelastine or cyproheptadine
 15. The composition according to claim 9 wherein said inflammatory disease is superficial vasodilator “flush” syndrome, said composition comprising a non-bovine proteoglycan, a flavonoid, bitter willow bark extract, and, optionally, cyproheptadine or azatadine.
 16. The composition according to claim 9, wherein said inflammatory disease is multiple sclerosis, said composition comprising quercetin or myricetin, hydroxyzine, and, optionally, caffeine, SAM and interferon-beta.
 17. The composition according to claim 9, wherein said inflammatory disease is migrain headaches, and said composition comprises non-bovine chondroitin sulfate, quercetin, and azatadine
 18. The composition according to claim 1, said composition being for oral use, comprising 150-300 mg per capsule or tablet of each of non-bovine chondroitin sulfate, quercetin and D-glucosamine sulfate, with 900-1200 mg of unrefined olive kernel extract, and, optionally, 100-200 mg sodium hyaluronate and/or 100 mg SAM.
 19. The composition according to claim 1, said composition consisting of an ointment or cream for topical application, comprising, in % by weight, non-bovine chondroitin sulfate, 5; D-glucosamine sulfate, 5; quercetin, 3; sodium hyaluronate 5; bitter willow bark extract 5; and unrefined kernel olive oil,
 15. 20. The composition according to claim 19 supplemented by at least one of the histamine-1 receptor antagonists diphenhydramine, hydroxyzine, azelastine, azatadine r cyproheptadine, 1-5 mg %.
 21. The composition according to claim 1, said composition compromising a mouth wash composition, consisting of non-bovine chondroitin sulfate and quercetin, each 0.3-0.4 M, and, optionally, at least one of D-glucosamine sulfate, 0.4 M and SAM, 0.15 M, in a mouth wash vehicle.
 22. The composition according to claim 1, said composition consisting of a tooth paste, comprising, in mg %, non-bovine chondroitin sulfate, 5; quercetin, 3; and, optionally, D-glucosamine sulfate, 5, in a tooth paste vehicle.
 23. The composition according to claim 1, said composition consisting of a sunscreen composition, comprising, in mg %, non-bovine chondroitin sulfate, 5; quercetin 3; and at least one of D-glucosamine sulfate, 5, and titaniun dioxide, 5, in a sun screen vehicle.
 24. The composition according to claim 1, for use in treating migraine headaches, said composition comprising, in mg, non-bovine chondroitin sulfate, 50; guercetin, 100; azatadine ,4; and, optionally, a CRH antagonist.
 25. The composition according to claim 1, said composition comprising, in mg, non-bovine chondroitin sulfate, 50: quercetin, 400; hydroxyzine, 50; and, optionally, a CRH antagonist.
 26. The composition according to claim 1, said composition comprising, in mg, non-bovine chondroitin sulfate, 100; D-glucosamine sulfate, 50; quercetin, 100; and unrefined olive kernel extract, 900-1200.
 27. The composition according to claim 1, comprising, in mg %, non-bovine chondroitin sulfate, 5; D-glucosamine sulfate, 5; quercetin, 3; in 900-1200 mg of unrefined olive kernel extract.
 28. The composition according to claim 1, wherein said inflammatory disease is cancer and wherein said composition is designed for oral use, comprising 25-50 mg of genistein and 150-300 mg of quercetin, in 900-1200 mg unrefined kernel olive oil.
 29. The composition according to claim 1, wherein said inflammatory disease is atherosclerosis with or without myocardial ischemia, comprising 100-300 mg each of non-bovine chondroitin sulfate, myricetin, folic acid and SAM, in 900-1200 mg unrefined kernel olive extract, in a vehicle for oral use.
 30. The composition according to claim 1, wherein said inflammatory disease is interstitial cystitis or prostatitis, said composition comprising, in mg, 100-300 of non-bovine chondroitin sulfate, 50-300 D-glucosamine sulfate, 100-300 of sodium hyaluronate, and 100-400 quercetin, 900-1200 unrefined olive kernel extract, in a vehicle for oral use.
 31. The composition according to claim 1, wherein said inflammatory disease is multiple sclerosis, said composition comprising, in mg, 50-300 each of non-bovine chondroitin sulfate, myricetin, hydroxyzine and SAM, 900-1200 of unrefined olive kernel extract, and, optionally, interferon-beta, in a vehicle for oral use.
 32. The composition according to claim 1, said composition comprising, in mg, non-bovine chondroitin sulfate 500; myricetin 300; and diphenhydramine, 5 mg %.
 33. The composition according to claim 1, said composition comprising, in mg, non-bovine chondroitin sulfate, 50; kaempferol, 100; SAM, 50; folic acid, 50; niacin, 100; and unrefined olive kernel extract, 900-1200.
 34. The composition according to claim 1, wherein said inflammatory disease is superficial vasodilation flush syndrome, said composition comprising 50 mg non-bovine chondroitin sulfate, 150 mg quercetin, 5% by weight bitter willow bark extract, and, optionally, 4 mg cyproheptadine or azatadine.
 35. The composition according to claim 1, wherein said inflammatory disease is skin allergy, said composition comprising, in % by weight, 5 each of aloe vera, non-bovine chondroitin sulfate and alpha-tocopherol, 15 of unrefined olive kernel extract, and, optionally, azelastine.
 36. The composition according to claim 1, wherein said inflammatory disease in allergy or allergic asthma, comprising 500 mg of myricetin, 200 mg of chondroitin sulfate, and, optionally, azelastine or hydroxyzine.
 37. The composition according to claim 36, in an aerosol vehicle.
 38. The composition according to claim 1, wherein said inflammatory disease is a hormonally-dependent cancer, comprising, in mg, 150 quercetin, 50 genestein, and, optionally, 10 tamoxifen or raloxifen.
 39. The composition according to claim 1, wherein said inflammatory disease is allergic conjunctivitis, comprising quercetin 0.05%, chondroitin sulfate 2.0%, and, optionally, azelastine 0.05%. 